Nine novel pathogenic germline mutations inMLH1,MSH2,MSH6andPMS2in families with Lynch syndrome

Rahner, Nils; Friedrichs, Nicolaus; Wehner, Maria; Steinke, Verena; Aretz, Stefan; Friedl, Waltraut; Buettner, Reinhard; Mangold, Elisabeth; Propping, Peter; Walldorf, Constanze

doi:10.1080/02841860701230217

Cited by 12 publications

(7 citation statements)

References 18 publications

(14 reference statements)

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“…The mutation detection rate was significantly higher (73%) if only MSI-H cases were considered. Although no point mutations were detected in the main MMR genes (MLH1/MSH2), in the remaining 14 patients with MSI-H or MSI-L tumors, the causes of the disease were likely to be other types of mutation, including re-arrangements, deletions or duplications in these same genes (22) or mutations in other MMR genes (PMS2, MSH6 and MLH3) (23,24), which were not detectable in the present study.…”

Section: Discussioncontrasting

confidence: 67%

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

Duraturo

Liccardo

Cavallo

et al. 2015

International Journal of Molecular Medicine

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Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L). These 26 patients were then screened for MLH1 and MSH2 germ-line mutations. Germ-line mutations in these genes were detected in 11/15 patients with MSI-H tumors (73%) and in 1/11 patients with MSI-L tumors (9%). Overall, 11 germ-line mutations in 12/26 analyzed patients (46%) in these genes were identified. Two of these mutations are novel genetic MLH1 variants not previously described in the literature, c.438A>G and c.1844T>C. A combination of computational approaches, co-segregation analysis and RNA assay suggested that these novel mutations, silent and missense, respectively, were probably pathogenic. The findings of the present study further emphasized the requirement for genetic testing in patients with a risk for hereditary CRC and has broadened the spectrum of known mutations of the MLH1 gene.

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Section: Discussioncontrasting

confidence: 67%

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

Duraturo

Liccardo

Cavallo

et al. 2015

International Journal of Molecular Medicine

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“…Age of onset was 5 years in both children, and one child did not have any cancer at the time of diagnosis [12]. Together with three previously described children with CMMRD and SLE [13][14][15], these cases indicate that pediatric onset SLE should be considered a diagnostic criterion of CMMRD, and CMMRD testing should be offered if additional features are present [1]. This might aid early diagnosis, but treatment of SLE in these patients may be challenging as the immune checkpoint inhibitors currently under investigation as a treatment for CMMRDrelated cancers could cause SLE to flare, while steroid treatment for SLE may lessen the effect of immune checkpoint inhibitors.…”

Section: Cmmrd and Early-onset Systemic Lupus Erythematosusmentioning

confidence: 56%

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

et al. 2020

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Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition associated with a high risk of cancer in children, adolescents and young adults. CMMRD is caused by homozygous or compound heterozygous pathogenic germline variants in one of four mismatch repair (MMR) genes (i.e., MLH1, MSH2, MSH6 and PMS2) [1], whereas mono-allelic (heterozygous) MMR gene variants result in autosomal dominant Lynch syndrome [2]. Lynch syndrome is one of the most common cancer predisposition syndromes and in adults leads to an increased risk of colorectal cancer, endometrial cancer and other malignancies [2]. By contrast, CMMRD is rare and leads to an increased risk of brain tumors, hematological malignancies, colorectal cancer and a wide range of other cancers in children, adolescents and young adults [1]. In addition, most patients with CMMRD have non-neoplastic features, with multiple café-au-lait maculae (CALM) being the most prevalent [1, 3]. This report summarizes the 5th meeting held by the 'Care for CMMRD' (C4CMMRD) consortium in Leiden, the Netherlands, on July 6th 2019. The consortium was established in 2013 with a number of explicit goals, including

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“…This mutation caused a splicing defect; as a result, exon 10 was missing and translation was prematurely terminated (13). No mutations were detected in MSH2.…”

Section: Patientmentioning

confidence: 99%

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea

Kim¹,

Choe²,

KimCho³

et al. 2010

BMB Reports

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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed with colorectal cancer and had subsequently undergone surgery. Five Lynch syndrome patients carried germline mutations in MLH1 or MSH2. Two of these were identified as known mutations in MLH1: deletion of exon 10 and a point mutation (V384D). The remaining three patients exhibited novel mutations: a duplication (937_942dupGAAGTT) in MLH1; deletion of exons 8, 9, and 10; and a point mutation in MLH1 (

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Nine novel pathogenic germline mutations inMLH1,MSH2,MSH6andPMS2in families with Lynch syndrome

Cited by 12 publications

References 18 publications

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea

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